Our long-term objective is to target the DNA polymerase zeta (Pol zeta) mutagenesis pathway as a novel strategy for cancer prevention. Mutagenesis is an important factor during the initiation and progression of human cancer. Without mutation, most, if not all, cancers would not form. DNA damage, either spontaneously formed or environmentally induced, is a major source of mutagenesis. In the yeast S. cerevisiae, the majority of DNA damage-induced mutations and some spontaneous mutations are generated through the Pol zeta mutagenesis pathway. Rev3 strongly interacts with Rev7, forming a tight protein complex designated as Pol zeta. Pol zeta is required for damage-induced mutagenesis and is thought to function during translesion synthesis opposite the damaged DNA template. Humans contain Pol zeta. Furthermore, recent studies suggest that this Pol zeta pathway also plays a major role in damage-induced mutagenesis in humans. Thus, we hypothesize that, by inhibiting DNA damage-induced mutagenesis, the Pol zeta mutagenesis pathway could provide a novel target for cancer prevention. We will use yeast as a model system to test the feasibility of using Pol zeta as a novel target for inhibiting mutagenesis by a small polypeptide agent. To do this, our specific aims are (1) to identify the Rev3-interacting polypeptide sequence of Rev7; (2) to test if the Rev3-interacting polypeptide is active as an inhibitory agent against damage-induced mutagenesis; and (3) to isolate novel Rev3-interacting polypeptides and subsequently to examine their inhibitory activities against damage-induced mutagenesis. Accomplishing this project would lead to more extensive development of targeting the human Pol zeta mutagenesis pathway for cancer prevention. If cancer can be prevented to occur, the benefits to humans will be enormous.